Infusion catheter assembly with reduced backflow

ABSTRACT

Catheters assemblies having structural configurations operable to reduce backflow along the catheter assembly track, and methods of making and using such catheter assemblies. Catheters assemblies in accordance with embodiments of the present invention find use in various applications including the treatment of acute and chronic medical conditions. An exemplary catheter assembly includes, in one illustrative embodiment, a flexible proximal catheter body portion, and a distal portion of a smaller diameter than the body portion. The distal portion includes a sealed distal tip or end and one or more side flow openings to permit flow of therapeutic substance from the catheter along an axis that is different than, e.g., skewed relative to, a longitudinal axis of the distal portion of the catheter assembly.

RELATED APPLICATION(S)

The present application is a divisional application of U.S. patentapplication Ser. No. 12/276,794 filed on 24 Nov. 2008, which claims thebenefit of U.S. Provisional Pat. App. No. 61/005,047, filed 30 Nov.2007, the contents of both applications being which are incorporated byreference herein in their entirety respective entireties.

TECHNICAL FIELD

The present invention relates generally to medical devices and, moreparticularly, to infusion devices (e.g., intraparenchymal catheters),and to systems and methods for making and using a catheter assembly.

BACKGROUND

Medical procedures involving access to the brain through a burr hole inthe skull are used to treat a variety of medical conditions. Forexample, burr holes may be formed to allow implantation of a catheter,e.g., an intraparenchymal (IPA) catheter, to deliver a therapeutic agent(infusate) to a target tissue region within a mammalian brain for thetreatment of neurological ailments.

Use of an IPA catheter to deliver a therapeutic agent to the braingenerally involves the insertion of the catheter into the brain anddispensing the agent at the desired target region. During a typicalimplantation procedure, an incision may be made in the scalp to exposethe patient's skull. After forming a burr hole through the skull, thecatheter may be inserted into the brain. To accurately place thecatheter and avoid unintended injury to the brain, surgeons typicallyuse stereotactic apparatus/procedures. One exemplary stereotacticapparatus is described in U.S. Pat. No. 4,350,159 to Gouda, which may beused to position, for example, an electrode. A cannula or needle may belocated and held with the stereotactic equipment, after which thecatheter may be inserted through the cannula. Once a distal tip of theIPA catheter is correctly located, the cannula may be removed, leavingthe catheter in place.

While effective for delivering substances to the desired location in thebody, care must be taken during implantation and therapy delivery toensure that backflow of the therapeutic agent is minimized. “Backflow,”as used herein, refers to portions of the therapeutic agent delivered bythe delivery tube (e.g., catheter) that tends to flow back along theouter diameter of the body of the delivery tube (e.g., towards itsproximal end) instead of infusing into the intended target tissue regionsurrounding the distal tip of the catheter.

While the degree of backflow may vary, it may become severe if theinfusate finds a path into the Cerebral Spinal Fluid (CSF). If such apath is formed, the infusion pressure may drop dramatically (e.g., untilit equals CSF pressure).

In addition to reducing the efficacy of the treatment (e.g., less thanthe desired volume of therapeutic agent is delivered to the intendedtarget tissue region), backflow may further result in substance deliveryto unintended regions of the body, e.g., other regions along thecatheter length. Moreover, the volume of substance that backflows isbasically wasted, a consequence which is particularly undesirable whenthe therapeutic agent is expensive or otherwise difficult to obtain.

Many conventional catheters are furthermore designed for treatment ofacute conditions. As a result, they are often configured for temporaryimplantation and are frequently constructed of generally rigid materialsthat are not amenable to modification (e.g., trimming) during the actualimplant procedure as may be required for longer term implantation. Theability to modify the catheter length would be advantageous forimplantation of catheters associated with long term (chronic) therapy.

SUMMARY

The present invention may overcome these and other issues by providingcatheter assemblies, systems, and methods operable to introduce an agentinto the body while reducing the occurrence of backflow of the agentalong the catheter assembly track. Catheter assemblies in accordancewith embodiments of the present invention may also be constructed oftrimmable materials so that they may be cut to the desired length duringthe implantation procedure. In one embodiment, a catheter assembly isprovided having a flexible tubular catheter body. The body has proximaland distal ends and includes an inner surface defining a lumen extendingbetween the proximal and distal ends. A rigid tubular needle is alsoprovided. The needle is partially located within the lumen of the bodyand extends outwardly from the distal end of the body. The needleincludes a nonporous outer surface defined by a diameter that is lessthan a diameter of an outer surface of the body, and a proximal endhaving a flange with a diameter larger than the diameter of the outersurface of the needle. The flange may be fixed relative to the innersurface of the body. The needle also includes a sealed distal tiplocated a preset distance beyond the distal end of the body. The needledefines a side flow aperture formed along the outer surface of theneedle and proximate to, but offset from, the sealed distal tip. Theside flow aperture is in fluid communication with the lumen of the body.

In another embodiment of the present invention, a catheter assembly isprovided having a flexible tubular catheter body with proximal anddistal ends. The body includes an inner surface defining a lumenextending between the proximal and distal ends. A guide tube is providedand fixed to the inner surface of the body near the distal end of thebody. A tubular needle is also provided and fixed to an inner surface ofthe guide tube such that it extends outwardly from a distal end of theguide tube. The needle includes an outer surface defined by a diameterthat is less than a diameter of an outer surface of the body; and asealed distal tip located a preset distance beyond the distal end of theguide tube. The needle further defines at least two side flow aperturesformed along the outer surface of the needle proximate to, but offsetfrom, the sealed distal tip. The side flow apertures are in fluidcommunication with the lumen of the body.

In still another embodiment of the invention, a method for delivery of atherapeutic substance to a target tissue region in a patient's brain isprovided. The method includes implanting into the target tissue region adistal end of a tubular needle of a catheter assembly. The catheterassembly includes a flexible tubular catheter body having proximal anddistal ends, the body having an inner surface defining a lumen extendingbetween the proximal and distal ends; and a guide tube fixed to theinner surface of the body near the distal end of the body. The assemblyalso includes the tubular needle. The tubular needle is fixed to aninner surface of the guide tube and extends outwardly from a distal endof the guide tube. In one embodiment, the tubular needle includes: anouter surface defined by a diameter that is less than a diameter of anouter surface of the body; and a sealed distal tip located a presetdistance beyond the distal end of the guide tube. The needle defines atleast two side flow apertures formed along the outer surface of theneedle proximate to, but offset from, the sealed distal tip, the sideflow apertures in fluid communication with the lumen of the body. Themethod further includes infusing the therapeutic substance into thetarget tissue region through the lumen at a constant flow rate viaconvection enhanced delivery from the side flow apertures.

The above summary is not intended to describe each embodiment or everyimplementation of the present invention. Rather, a more completeunderstanding of the invention will become apparent and appreciated byreference to the following Detailed Description of Exemplary Embodimentsand claims in view of the accompanying figures of the drawing.

BRIEF DESCRIPTION OF THE VIEWS OF THE DRAWING

The present invention will be further described with reference to thefigures of the drawing, wherein:

FIGS. 1A-1B illustrate enlarged views of a distal end of a diagrammaticcatheter (e.g., IPA catheter), wherein: FIG. 1A illustrates a desired ornormal distribution of therapeutic agent from a catheter duringconvection-enhanced delivery (CED); while FIG. 1B illustratesdistribution when backflow occurs;

FIGS. 2A-2B illustrates an implanted infusion system in accordance withone embodiment of the present invention, the system including anexemplary IPA catheter or catheter assembly having a distal tip fordelivering a therapeutic agent to a body, e.g., to the brain, wherein:FIG. 2A illustrates the IPA catheter implanted within the body; and FIG.2B illustrates the catheter removed from the body;

FIGS. 3A-3B illustrate the IPA catheter of FIGS. 2A-2B, wherein: FIG. 3Aillustrates a partial section view of a distal portion of the catheter;and FIG. 3B illustrates an enlarged partial side elevation view of thedistal portion;

FIGS. 3C-3E illustrate a variation of the IPA catheter embodiment ofFIGS. 3A-3B, wherein: FIG. 3C illustrates an exploded side elevationview; FIG. 3D illustrates a section view of the catheter as assembled;and FIG. 3E illustrates an enlarged section view of a portion of thecatheter;

FIGS. 4A-4D illustrate an IPA catheter in accordance with anotherembodiment of the invention, wherein: FIG. 4A is a partial sideelevation view of the catheter; FIG. 4B is a similar view in sectionillustrating a guide tube of the catheter; and FIGS. 4C and 4D areenlarged portions of the section view of FIG. 4B illustrating a proximaland a distal end, respectively, of the guide tube;

FIG. 5 is a side elevation view of a catheter body of the catheter ofFIGS. 4A-4D;

FIG. 6 is a enlarged and partial cut-away view of the guide tube of thecatheter of FIGS. 4A-4D;

FIGS. 7A-7C illustrate a needle of the catheter of FIGS. 4A-4D, wherein:FIG. 7A is a side elevation view; FIG. 7B is an enlarged view of aproximal end of the needle; and FIG. 7C is an enlarged view of a distalend of the needle;

FIG. 8 is an exploded section view of the catheter of FIGS. 4A-4Dillustrating a method of making the catheter in accordance with oneembodiment of the invention;

FIG. 9 is a section view of an IPA catheter in accordance with yetanother embodiment of the invention;

FIGS. 10A-10B illustrate an IPA catheter in accordance with anotherembodiment of the invention, wherein: FIG. 10A illustrates a partialperspective section view of a distal portion of the catheter; and FIG.10B illustrates an enlarged partial perspective view of the distalportion;

FIG. 10C illustrates a section view of an IPA catheter assembly inaccordance with still another embodiment of the invention;

FIGS. 11A-11B illustrate an IPA catheter in accordance with yet anotherembodiment of the invention, wherein: FIG. 11A illustrates a sectionview of a distal portion of the catheter with a balloon of the catheterdeflated; and FIG. 11B illustrates generally the same view with theballoon inflated;

FIG. 12 illustrates an enlarged view of a distal portion of an IPAcatheter in accordance with yet another embodiment of the invention;

FIGS. 13A-13D are MRI images of contrast dispersion occurring withconventional uniform diameter, axial flow catheters when implanted infour different in vivo specimens; and

FIG. 14 illustrates an MRI image of contrast dispersion in an in vivosubject when using a catheter assembly constructed in accordance withone embodiment of the present invention.

The figures are rendered primarily for clarity and, as a result, are notnecessarily drawn to scale.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

In the following detailed description of illustrative embodiments of theinvention, reference is made to the accompanying figures of the drawingwhich form a part hereof, and in which are shown, by way ofillustration, specific embodiments in which the invention may bepracticed. It is to be understood that other embodiments may be utilizedand structural changes may be made without departing from the scope ofthe present invention.

Embodiments of the present invention are directed generally to fluidconduits such as infusion catheter assemblies (also be referred toherein merely as “catheters”) and to systems and methods for using thesame. For example, embodiments of the present invention may include adelivery tube, e.g., IPA catheter, for delivering a therapeutic agent toa region of the body. As further described below, embodiments of thepresent invention may reduce backflow of the therapeutic agent along thedelivery track of the delivery tube/catheter body, thus delivering aprecise, predetermined volume of therapeutic agent to a target tissueregion of the body. Other embodiments of the invention may be directedto methods for making such catheter assemblies.

Backflow may occur when a fluidic seal between the delivery tube andsurrounding tissue is broken. To illustrate backflow, FIG. 1A shows adesired spherical distribution 50 of a substance into tissue 51 from anaxial distal end 52 of a catheter 54, while FIG. 1B illustrates a“tear-drop” distribution 56 that may occur when a catheter experiencesbackflow. Although somewhat difficult to measure directly, backflow maybe detected by observation of substance dispersion under, for example,magnetic resonance imaging (MRI). While backflow may occur with manydelivery techniques, it may be particularly problematic duringconvection enhanced delivery (CED) in the treatment of target tissuewithin mammalian brains. Convection enhanced delivery (CED) to the brainuses bulk flow in the extracellular space that results from a pressuregradient to significantly enhance tissue penetration of the deliveredsubstance.

In some embodiments of the present invention, catheters are providedthat include a distal end having flow openings or apertures oriented atan angle that is skewed relative to (or otherwise nonparallel to) alongitudinal axis of the distal portion of the catheter. As a result,the catheter may be configured such that fluid exiting the catheter doesso in a nonaxial manner, e.g., at an angle of about 90 degrees to alongitudinal axis of the distal portion of the catheter.

In some embodiments, the nonaxial apertures may be provided by a tipmember, e.g., insert, that fits within the distal end of the catheterbody and effectively blocks axial flow. The flow apertures may then beformed on an outer surface of the insert. In other embodiments, the tipmember may be a closed- or sealed-end needle secured relative to thedistal end of the catheter body. The needle may then define side flowapertures as further described below. The apertures may be offset aslight distance from the most distal end of the catheter (e.g., from thedistal end of the insert or needle) as shown in the figures anddescribed below. These side flow openings are believed to assist withreducing backflow along the delivery track of the catheter.

In still other embodiments, the catheter may include an obstructiveelement positioned along the body of the catheter and spaced away fromthe distal end/flow openings by a preset distance. The obstructiveelement may interfere with the flow of fluid (e.g., therapeutic agent)back along the catheter delivery track.

Catheters in accordance with embodiments of the present invention mayalso provide a catheter body that may be easily trimmed, e.g., sheared,to the correct length during the implantation procedure. That is,catheters in accordance with embodiments of the present invention mayinclude a body that is made from a material that is shearable ortrimmable. A catheter that is “shearable” or “trimmable,” as these termsare used herein, may be cleanly cut via a shearing or scissoring actionwithout the use of mandrels or secondary tools and without damaging thecatheter body itself (e.g., occluding the lumen, splintering orweakening of the catheter material). The ability to trim the proximalend of the catheter is beneficial to implantations for chronic treatmentas it allows the surgeon to easily and accurately size the catheterlength during the implantation procedure.

FIG. 2A illustrates an exemplary implantable medical system (e.g., abrain infusion catheter system 100) that may utilize an IPA catheter 200in accordance with one embodiment of the present invention. FIG. 2Aillustrates the IPA catheter implanted within the body, while FIG. 2Billustrates the catheter removed from the body. While shown as part of acompletely implanted system, applications where a portion of thecatheter 200 is external to the body are also contemplated.

The illustrated infusion system may include a first medical tube, e.g.,the IPA catheter or catheter assembly 200, and an optional secondmedical tube, e.g., delivery catheter 104. The delivery catheter 104 mayhave an end 106 coupled to a reservoir containing a volume of atherapeutic agent (e.g., an infusion pump 108, which may be identical orsimilar to the SynchroMed® II programmable infusion pump distributed byMedtronic, Inc., of Minneapolis, Minn. USA). In the illustratedembodiment, the pump 108 is implanted within the body 101. However,external reservoirs, e.g., external pumps, syringes, drip bags, etc.,may also be used.

The IPA catheter 200 may have its distal portion 202 implanted, via aburr hole 112, at a predetermined location within the body 101, e.g.,brain 114, of the patient. In some embodiments, a burr hole anchor 116may be used to secure a proximal end 204 of the catheter 200 relative tothe cranium and permit connection to a corresponding proximate end 120of the delivery catheter 104. Thus, the pump 108 may be fluidly coupledto the catheter 200.

The system 100 may, in one embodiment, be configured to deliver atherapeutic agent for the treatment of chronic brain and central nervoussystem disorders, e.g., Huntington's disease. The therapeutic agent maybe delivered, via the catheter assembly 200 (or 200′, 300, 400, 500,550, 600, or 700 as described below), from the pump 108 to the brain114. This application is not limiting, however, as the system may beconfigured to deliver other therapeutic agents either to the brain(e.g., such as agents for the treatment of Parkinson's or Alzheimer'sdisease) or to most any other area of the body without departing fromthe scope of the invention.

It is noted that the terms “comprises” and variations thereof do nothave a limiting meaning where these terms appear in the accompanyingdescription. Moreover, “a,” “an,” “the,” “at least one,” and “one ormore” are used interchangeably herein.

Relative terms such as left, right, forward, rearward, top, bottom,side, upper, lower, horizontal, vertical, and the like may be usedherein and, if so, are from the perspective observed in the particularfigure. These terms are used only to simplify the description, however,and not to limit the scope of the invention in any way.

With this general overview, the following description will addressvarious catheter embodiments, as well as methods for making and usingthe same. While these embodiments may be described with some degree ofspecificity, they are nonetheless intended to be exemplary. Those ofskill in the art will recognize that other embodiments are possiblewithout departing from the scope of the invention.

FIGS. 3A and 3B illustrate enlarged views of a distal portion 202 of theexemplary IPA catheter 200 of FIGS. 2A and 2B. FIG. 3A illustrates asection view of the distal portion 202, while FIG. 3B illustrates asimilar side elevation view.

The catheter 200 may include a flexible tubular catheter body 206. Inone embodiment, the body 206 is constructed of an elastomeric,homogeneous, and shearable material. An optional insert, e.g., annularguide member or tube 208, may be attached to the body (e.g., to an innersurface of a bore or lumen 218 of the body 206) near the body's distalend. In one embodiment, the guide tube is bonded to the catheter body.For instance, in one embodiment, the guide tube is reflow bonded to thecatheter body. In another embodiment, the guide tube is bonded to thecatheter body with an appropriate adhesive selected to adhere the tubeto the catheter body and to maintain adhesion while the catheterassembly is implanted in the target tissue region. However, theseconfigurations are not limiting. As shown in FIGS. 3A and 3B, the guidetube 208 may include a flange or flange portion 210 that abuts thedistal end of the body 206 when the guide tube 208 is fully inserted.The guide tube may further include a grooved or roughened outer surface(described in more detail with respect to the guide tube 208′ below) tofacilitate bonding with the catheter body.

A rigid and hollow tubular tip member may be partially located withinthe lumen 218 of the body 206 and extend outwardly from its distal end.In the illustrated embodiment, the tip member is a nonporous tube orneedle 212. The needle 212 may be fixed or otherwise bonded to the guidetube 208 such that it extends beyond the distal end of the guide tube asillustrated in FIG. 3A. In one embodiment, the needle 212, e.g., itsdistal tip 202 a, is configured to extend a preset distance 214 beyondthe distal end of the body 206 and guide tube 208 (e.g., beyond theflange 210 of the guide tube) for reasons that are further explainedbelow.

The distal tip or end 202 a of the needle 212 (which forms themost-distal end of the catheter 200) may be sealed or closed (e.g.,rounded) as shown in FIG. 3B. This axial closure of the needle preventsaxial flow from the needle tip. However, the needle 212 may include oneor more flow openings or apertures offset from the sealed distal tip 202a, the openings each having an axis that forms an angle other than zerodegrees with a longitudinal axis of the catheter body/needle. Forinstance, one or more side flow openings 216 each having an axis thatforms an angle of about 90 degrees with (e.g., is normal to) thelongitudinal axis of the needle may be provided. These side flowopenings are fluidly coupled to the lumen 218 of the catheter body sothat therapeutic substance flowing through the lumen may pass into thelumen of the needle 212 and out through the opening(s) 216.

The configuration of the catheter 200 provides several benefits. Forinstance, by utilizing a closed end 202 a, the catheter may be insertedinto the body with little or no tissue coring. In addition to reducedcoring, the relatively smaller (compared to the catheter body) diameterof the protruding needle 212 minimizes the diameter of the most distalportion of the catheter 200, which may reduce tissue trauma duringcatheter introduction. The smaller diameter of the needle 212 mayfurther contribute to reduced backflow as increased backflow has beenassociated with increased diameter of the catheter, as well as withincreased infusate flow rate (see, e.g., Morrison et al., Focal DeliveryDuring Direct Infusion to Brain; Role of Flow Rate, Catheter Diameter,and Tissue Mechanics, Am J Physiol Regul Integr Comp Physiol 277,R1218-R1229 (1999)).

Moreover, by utilizing side flow opening(s) 216, the infusion peakpressure may potentially be reduced (as compared to an axial flowcatheter), which may further reduce backflow. Still further, the sideflow opening(s) may, in some embodiments, be relatively small, reducingthe opportunity for tissue in-growth.

The catheter 200 may further provide an obstructive element, e.g., ledge220, positioned along the catheter and spaced apart from the distal tipand side flow openings by a preset distance. The ledge may, in oneembodiment, be formed by the flange 210 of the guide tube 208 positionedat or near the distal end of the body such that the ledge is normal to alongitudinal axis of the guide tube and/or needle. The ledge 220 mayform a barrier capable of interfering with backflow 222 of therapeuticsubstance delivered by the catheter 200. For example, any volume ofsubstance 222 that tends to flow into any low pressure void existingbetween the needle 212 and the surrounding tissue and towards theproximal end of the catheter 200 may be obstructed by the radiallyprotruding ledge 220 as represented in FIG. 3B.

While not wishing to be bound to any particular configuration, thecatheter body 206 (like the other catheter bodies described herein) may,in one embodiment, be made from a shearable material such as 80 Shore Adurometer urethane and have an inner surface defined by an innerdiameter of about 0.024 inches (in) and an outer surface defined by anouter diameter of about 0.041 in. As a result, the proximal end of thecatheter body may be cut (e.g., shear cut), during the implantationprocedure, to provide the catheter with the desired length. Whiledescribed as urethane, the catheter body 206 may be made from othermaterials such as other urethanes, silicones, and blends of the same.

The guide tube 208, on the other hand, may be made from a material thatis substantially more rigid than the material of the body, e.g.,polyetheretherketone (PEEK) or 316 stainless steel. In the illustratedembodiment, the guide tube may have a length (including the flange 210)of about 0.2 in to about 0.5 in, e.g., about 0.4 in. However, relativesize of the guide tube, as well as the other components of the catheter,may be adapted to suite most any particular application.

The needle 212 may, in one embodiment, be made from 316 stainless steelhypodermic tubing and have a proximal end that is fixed, when assembled,at a location within the lumen of the body 206 and located at or nearthe proximal end of the guide tube (or the optional sleeve 213 when thelatter is included). The needle 212 may further have an inner surfacedefined by a diameter of about 0.004 in, and an outer surface defined bya diameter of about 0.006 in to about 0.010 in, e.g., about 0.008 in(e.g., a 33 gage needle). Accordingly, the diameter of the outer surfaceof the needle 212 is less than the diameter of the outer surface of thebody 206. In some embodiments, a ratio of the diameter of the outersurface of the tubular catheter body 206 to the diameter of the outersurface of the needle may be about 4:1 to about 6:1, e.g., about 5:1.

In the illustrated embodiment, the one or more side flow openings 216may have a diameter of about 0.004 in. Moreover, the needle 212 may bebonded to the guide tube 208 with a cyanoacrylate adhesive. In anotherembodiment (see FIG. 3A), the sleeve 213 may be provided. The sleeve 213may be bonded to a proximal end of the guide tube 208 and also to theneedle 212, thereby securing the needle relative to the guide tube. Inyet other embodiments, the needle could be over-molded with the guidetube, negating the need for the sleeve 213.

Once again, while identified herein with some degree of specificity, thesizes, materials, and geometry of various components are understood tobe exemplary only and other sizes, materials, and geometries arecertainly possible without departing from the scope of the invention.

In yet other embodiments, a catheter 200′ similar to the catheter 200may be provided as shown in FIGS. 3C-3E. In this particular embodiment,identified components may be substantially similar or identical to thelike components of the catheter 200 except as otherwise described and/orillustrated herein.

As shown in FIG. 3C, the catheter 200′ may include a body 206′, a guidetube 208′ forming a flange 210′, a spacer 213′, and a needle 212′ havinga nonaxial opening 216′. Unlike the needle 212, however, the proximalend of the needle 212′ may be flanged, e.g., form a flange 215′ having adiameter larger than the diameter of the outer surface of the remainderof the needle. As a result, the needle 212′ may be fed through the guidetube 208′ after which the flange 215′ may seat near or against a portion(e.g., a land) of the lumen of the guide tube near its proximal end asshown in FIGS. 3D and 3E.

The spacer 213′ may be positioned within the catheter body 206′ suchthat a male portion 232′ slides into a female portion 234′ of the guidetube 208′ as shown in FIGS. 3D and 3E. The spacer 213′ may thus be usedto trap or otherwise mechanically secure the needle in place relative tothe catheter body 206′. The catheter body 206′ may then be reflowed(heat) bonded to both the guide tube 208′ and spacer 213′ to yield theassembly of FIG. 3D.

FIG. 3E illustrates an enlarged view of the guide tube 208′, the spacer213′, and the flange 215′ of the needle 212′. As illustrated in thisview, there may be a small, e.g., 0.003-0.004 in, gap between the distalend of the spacer 213′ and the bottom of the female portion 234′ of theguide tube 208′. Accordingly, the needle 212′ may be permitted someslight axial movement. In other embodiments, however, the spacer 213′could be positioned to press the needle 212′ against the guide tube208′.

In most other respects, the catheters 200 and 200′ are similar. Forinstance, they may both have a preset distance 214 (e.g., the distancethat the needle 212 extends beyond the flange 210) of about 0.2 in toabout 0.5 in), e.g., about 0.4 in. By providing a needle 212 (or 212′)that protrudes from and beyond a distal end of the catheter body 206 (or206′) as shown and described, the catheter may be implanted using acannula 226 (see FIG. 3B) having a distal end 228 that is positionable,e.g., by stereotactic equipment, a distance equal to the preset distance214 away from the target region 230. As a result, when the catheter 200is implanted through the cannula, the relatively narrow needle 212 isall that penetrates tissue beyond the distal end 228 of the cannula,i.e., there is no need to force the wider flange 210 and body 206through the tissue near the target region.

While exemplary needles 212 and 212′ are described as having particularlengths, such specific dimensions are not limiting. Rather, the distance214, e.g., the length of the needle 212, may vary depending on theparticular application. For instance, a longer needle may be beneficialin some applications as longer needles may provide increased flow ratefor a given needle diameter. Similarly, shorter needles may also beappropriate in some applications.

FIGS. 4A-8 illustrate enlarged views of a distal portion 302 of an IPAcatheter or catheter assembly 300 in accordance with another embodimentof the invention. The catheter 300 may be used in place of the catheters200 and 200′ in the system 100 of FIGS. 2A and 213. Moreover, relativedimensions, materials, etc. described with respect to the catheters 200and 200′ may also apply the catheter 300 unless otherwise noted herein.

FIG. 4A illustrates a side elevation view of the distal portion 302 ofthe catheter 300, while FIG. 4B illustrates a similar view in section.Once again, the catheter 300 may include a flexible and shearabletubular catheter body 306 having an inner surface and an outer surface,wherein the inner surface defines a lumen 318 extending between thebody's proximal and distal ends in a manner generally identical to thebodies (e.g., 206 and 206′) already described herein. A tubular insert,e.g., annular guide member or tube 308, may be fixed or otherwisesecured relative to the body (e.g., fixed to the inner surface of thelumen 318 of the body 306) near the body's distal end such that aproximal end of the guide tube is intermediate the proximal and distalends of the body. In one embodiment, the guide tube is bonded e.g.,reflow bonded, to the catheter body as further described below. However,such a configuration is not limiting.

As shown in FIGS. 4A-4D, the guide tube 308 may include a distal endhaving a flange or flange portion 310 that extends beyond the distal endof the body 306 and may abut the same when the guide tube is fullyinserted in the body.

In addition to the flange portion, the guide tube 308 may also form asleeve or sleeve portion having an inner surface and an outer surface.The outer surface 309 may be smooth or, alternatively, define one ormore grooves (e.g., circumferential grooves) as shown in FIG. 4D. Whileillustrated as incorporating grooves of generally semi-circular crosssection, this shape is not limiting as grooves of other shapes (e.g.,grooves of V-shaped cross section as shown in broken lines in FIG. 4D)are also possible without departing from the scope of the invention. Instill other embodiments, the surface 309 may merely be abraded orroughened. Such configurations may facilitate securing of the guide tube308 to the catheter body 306, e.g., by forming mechanical capture pointsor recesses into which inwardly extending portions of the body mayextend as shown in FIG. 4D. The inner surface 307 of the guide tube 308(see the enlarged view of the proximal end of the guide tube shown inFIG. 4C) may be defined by a bore 319 extending through the guide tube.In one embodiment, the bore may be a stepped bore forming a recessedland 311 to receive and contact a flange 315 of a needle as described inmore detail below.

As with the catheters 200 and 200′, a rigid, hollow tubular needle 312may be partially located within the lumen of the catheter body 306 andoperatively fixed relative to the body, e.g., fixed to an inner surfaceof the guide tube 308. Stated alternatively, the guide tube may beinterposed or positioned between the proximal end of the needle 312 andthe inner surface of the body 306. The needle 312 may, like the needles212 and 212′, extend or protrude outwardly from the distal end of theguide tube such that a sealed distal tip 302 a of the needle is locateda preset distance 314 beyond the distal end of the catheter body/guidetube flange 310 as illustrated in FIGS. 4A and 4B.

Once again, the needle 312 may be nonporous and incorporate the sealed,rounded distal tip or end 302 a (which forms the most-distal end of thecatheter 300) as shown in FIGS. 4A-4B. As with the other needleembodiments described herein, closure of the needle tip prevents directaxial flow from the needle. However, as with the needles 212 and 212′,the needle 312 may include one or more, e.g., two, side flow openings orapertures 316 formed along an outer surface of the needle and proximateto, but offset from, the sealed distal tip. Like the needles 212 and212′, the flow apertures may each have an axis that is, nonparallel to,e.g., normal to, the longitudinal axis of the catheter and/or theneedle. The aperture(s) 316 are again in fluid communication with thelumen 318 of the body 306 such that therapeutic substance flowingthrough the lumen may pass into the needle 312 (e.g., the lumen of theneedle) and out through the aperture(s) 316.

The configuration of the catheter 300 provides benefits similar to thosealready described above with respect to the catheters 200 and 200′. Forinstance, like the catheters 200 and 200′, the needle 312 of thecatheter 300 may have an outer surface defined by a diameter that isless than a diameter of the outer surface of the body 306. Thus, thecatheter 300 provides an obstructive element, e.g., ledge 320, which maybe formed by the flange portion 310 of the guide tube 308. The ledge 320may again form a barrier that potentially reduces, via interference,backflow of therapeutic substance delivered by the catheter 300.Moreover, the relative sizes of the needle 312 and catheter body 306, aswell as the side position of the flow opening(s) 316, may contribute toimproved backflow characteristics.

FIGS. 5-9 illustrate the exemplary individual components of the catheter300. FIG. 5 illustrates the flexible and shearable body 306; FIG. 6illustrates an enlarged and partial cut-away view of the guide tube 308;FIG. 7A illustrates the needle 312; and FIGS. 7B and 7C illustrateenlarged views of a proximal end and distal end, respectively, of theneedle 312.

As already described above with respect to the catheters 200 and 200′,the catheter body 306 may, in one embodiment, be made of a material suchas urethane. As a result, the proximal end of the catheter may be cut(e.g., shear cut) during implantation to provide the catheter with thedesired length.

The guide tube 308 may be made from a variety of materials including,for example, PEEK or other thermoplastic materials. In some embodiments,the guide tube may again have a length (including the flange 310) ofabout 0.2 in to about 0.4 in. As illustrated in FIG. 6, the recessedland 311 may be defined by the transition existing between the largerbore diameter at the proximal end of the guide tube 308, and the smallerbore diameter extending towards the distal end.

The exemplary needle 312 may, in one embodiment, be made from 33 gage316 hypodermic tubing having its distal tip sealed or capped to limit orprevent direct axial flow from the needle. In one embodiment, the distalend of the needle is sealed through a cold forming process or an orbitalriveting operation, although other capping methods may be used. The sideflow opening(s) 316 may be formed in the needle proximate to, but offsetfrom, the distal end (e.g., by a distance 317 (FIG. 7C) of about 0.015in) and, like the openings 216′, have a diameter of about 0.004 in(generally equal to the inner diameter of the needle). The openings maybe formed by a guided drilling process or, alternatively, a lasermachining process. While other embodiments are possible, the illustratedneedle 312 includes two side flow openings 316 that are diametricallyopposed.

While effective as a delivery conduit, needles 312 constructed ofstainless steel may produce undesirable artifacts when viewed under MRI.As a result, some embodiments may utilize a needle 312 constructed ofplatinum (Pt)-iridium (Ir) alloy. For example, a needle made from 90Pt-10 Ir or 80 Pl-20 Ir alloy are contemplated. Needles produced fromthese alloys may reduce undesirable MRI artifacts without sacrificingoverall catheter performance.

As perhaps best illustrated in FIGS. 4C and 7B, the needle 312, like theneedle 212′, may further include the flange 315 at its proximal end. Theproximal end of the needle, e.g., the flange 315, may, once again, havea diameter larger than the diameter of the outer surface of the needleand may be fixed relative to the inner surface of the body 306, e.g.,fixed directly to the inner surface of the guide tube 308. That is, theflange 315 may, upon insertion of the distal end of the needle 312 intothe proximal end of the guide tube 308 (via the bore 319), function as amechanical stop once the flange abuts the land 311 of the guide tube.Moreover, the flange at the proximal end of the needle 312 may permitthe needle to be mechanically secured directly to an inner surface ofthe guide tube 308 as further described below.

As with the other embodiments illustrated herein, the distal end of theneedle 312 may extend beyond the catheter body 306 and flange 310 by apreset distance 314 (e.g., about 0.4 in) when the catheter is assembledfor reasons already described herein (see, e.g., implantation of thecatheter 200 with the cannula 226 of FIG. 3B).

An exemplary method of assembling the components of the catheter 300will now be described primarily with reference to FIG. 8. The needle312, e.g., the distal tip or end 302 a of the needle, may be insertedinto the guide tube 308 via the proximal end of the bore 319 as shown inFIG. 8. Upon complete insertion, the flange 315 of the needle maycontact and rest upon the land 311 of the guide tube 308. At this point,the distal end of the needle may protrude the preset distance 314 beyondthe distal end of the guide tube. Through a thermal process, the outersurface of the needle 312 (e.g., the flanged proximal end) may be fusedor otherwise bonded to the inner surface of the guide tube 308. In oneembodiment, this is accomplished by placing a soldering iron tip intothe proximal end of the needle 312 and fusing the flange 315 of theneedle to the inner surface of the guide tube. In one embodimentutilizing a Pl-Ir needle and a PEEK guide tube, the soldering iron mayheat the needle locally to about 670 degrees Fahrenheit (F) to melt it,whereupon the needle fuses to the guide tube upon cooling. Such aprocess not only mechanically interlocks the needle to the guide tube,but furthermore desirably seals any annular flow path between the needleand the guide tube without requiring adhesives or other intermediatematerials.

Once the needle 312 is attached to the guide tube 308, the proximal endof the guide tube may be inserted into the distal end of the body 306(into the lumen 318 of the body) until the flange portion 310 abuts thedistal end of the body (see FIG. 4A). A reflow operation may then beperformed to the catheter body 306 to fix or otherwise mechanicallysecure the guide tube 308 relative to the body (e.g., to the innersurface of the body). For example, in one embodiment, a section of heatshrink tubing 324 may be placed over the distal end of the body 306 ofthe catheter 300 as shown in FIG. 8. A heating element 325 (e.g., oven)may then heat the tubing 324 and the body 306. Upon reaching a thresholdtemperature (e.g., about 310 degrees F. for a urethane body), the body306 may begin to reflow and bond to the guide tube 308. Reflow of thebody material may result in an effective mechanical interlock or captureof the guide tube 308 with the inner surface of the body 306 as bodymaterial flows into the grooves 309 of the outer surface of the guidetube (see, e.g., FIG. 4D). The reflow operation may also effectivelyseal any annular flow path between the guide tube and the catheter body,generally preventing flow at the interface of these two components. Atthe completion of the reflowing operation, the heat element isdeactivated and removed. After cooling, the heat shrink tubing 324 maybe sliced and removed from the body, yielding the catheter 300 asillustrated in FIG. 4A.

While the use of the guide tube 308 is beneficial when a relativelylarge difference exists between the inner diameter of the catheter body306 and the outer diameter of the needle 312, it may be unnecessary inother applications where this difference is slight. For example, FIG. 9illustrates an exemplary catheter 400 similar to the catheter 300. Thatis, it includes a flexible and shearable catheter body 406 with a needle412 extending from a distal end of the body. The needle 412 may besubstantially identical to the needle 312 already described herein.However, the catheter body 406 may have an inner diameter that issmaller than that of the body 306 (e.g., the catheter body may have athicker wall). In this instance, the needle may be located at thedesired position within the body 306 as shown in FIG. 9. At this point,the body may be reflowed (e.g., in a manner similar to that describedabove with reference to the catheter 300) until it bonds with the needle412. That is, the needle 412, e.g., the flange 415, may be fixed orotherwise secured directly to the inner surface of the body 406. Whileillustrated herein as using a needle having a flange 415, such aconfiguration is not limiting. That is, a flangeless needle (not shown)could also be used in place of the flanged needle 412 without departingfrom the scope of the invention. The catheter body 406 may, in thisembodiment, be used to form an obstructive element, e.g., ledge 420,similar in function to the obstructive elements already describedherein.

The catheters 200, 200′, 300, and 400 described above provide aneffective construction to reduce backflow along the catheter track.However, other configurations are also contemplated that may providebenefits similar to those already described herein. For example, FIGS.10A and 10B illustrate enlarged views of a distal portion 502 of an IPAcatheter 500 in accordance with another embodiment of the invention.Except as described herein, the catheter 500 may be used in place of thecatheters 200, 200′, 300, and 400 within the system 100.

FIG. 10A illustrates a perspective section view of the distal portion502 of the catheter 500, while FIG. 10B illustrates a correspondingperspective view. The catheter 500 may include a flexible tubular body506, an insert (e.g., guide tube 508), and a tip member or needle 512that may be substantially similar or identical to the like componentsillustrated and described with respect to the catheters 200, 200′, 300,or 400. For example, the guide tube 508 may include a flange 510 thatabuts the distal end of the body 506 when the guide tube is fullyinserted and secured to the body. Moreover, the needle 512 may extendbeyond the distal end of the guide tube 508 in a manner similar to thatof the catheters 200, 200′, 300, and 400. In the illustrated embodiment,the needle 512 may extend a predetermined distance 514 (e.g., about 0.4in) beyond an expanding cup or cup member 532 (described below andattached at or near the distal end of the catheter body) and include aclosed distal end 502 a similar to the needles described elsewhereherein. Therapeutic substance may flow through a lumen formed by theinner surface of the body 506 and a lumen of the needle 512 and outthrough nonaxial side flow opening(s) 516.

The catheter 500, unlike the catheter described above, however, may alsoinclude the cup 532. In one embodiment, the cup 532 may be made from arelatively flexible material such as silicone. The cup may thus collapsefor fitting within a delivery/removal cannula 526 (see FIG. 10B), butmay expand as illustrated in FIGS. 10A and 10B when the cannula iswithdrawn. The cup 532 may be secured or otherwise bonded to the flange510 of the guide tube 508 and/or the needle 512, or alternatively, to anouter surface of the catheter body 506. In one embodiment, the cup 532may have a maximum or unconstrained O.D. of about 0.08 in (when usedwith a catheter otherwise sized as described above with reference to thecatheter 200).

Like the ledge 220 provided by the catheter 200, the cup 532 of thecatheter 500 also provides an obstructive element, e.g., an undercutledge 520. The undercut ledge may, in some applications, further assistwith backflow prevention as already described above. Moreover, an outersurface of the cup 532 may, upon withdrawal of the cannula 526 andexpansion of the cup, generate a compressive seal with the immediatelysurrounding tissue. This seal may further assist with reducing catheterbackflow.

The catheter 500 may be removed by application of a traction force. Uponwithdrawal, the shape of the cup 532 may be such that it collapses to asize about equal to the outer diameter of the catheter body 506 and thuscan withdraw through the catheter passageway without difficulty.Alternatively, the cannula 526 may be placed over the catheter body 506and cup 532. Once again, the shape of the cup 532 may permit the cannulato slide over and squeeze the cup until the body and cup are containedwithin the cannula.

FIG. 10C illustrates a section view of an IPA catheter 550 similar inmany respects to the IPA catheter 500 of FIGS. 10A-10B and could be usedin place of the latter. The catheter 550 may once again include aflexible tubular body 556. A distal portion 552 of the catheter 550 maybe formed by an insert or guide tube 558 located within the distal endof the body 556. The insert 558, like the guide tube 508, may include aflange 560 that abuts the distal end of the body 556 as shown. While theinsert 558 may be similar in many respects to the guide tube 608, it mayfurther include an integral needle 562 defining a nonaxial side flowopening(s) 566. As FIG. 10C illustrates, the catheter 550, like thecatheter 500 described above, may also include the cup 582. The cup 582may be more conical in shape than the cup 532. However, itsfunctionality is generally the same as that described above with respectto the catheter 500. Therefore, further description of the catheter 550is not provided herein.

FIGS. 11A and 11B illustrate enlarged views of a distal portion 602 ofan IPA catheter 600 in accordance with yet another embodiment of theinvention. Once again, except as described herein, the catheter 600could be used in place of, the catheters 200, 200′, 300, 400, 500, and550 in the system 100.

FIG. 11A illustrates an inflatable balloon (described in more detailbelow) associated with the catheter in a deflated configuration, whileFIG. 11B illustrates the balloon inflated. The catheter 600 may, likethe others described herein, includes a flexible tubular body 606forming a lumen 618 through which therapeutic substance may bedelivered. Moreover, the catheter 600 includes an insert. However,rather than a guide tube arrangement and needle like that described, forexample, with respect to the catheters 200 and 300, the insert of thecatheter 600, like the insert 558, may form an axially closed tip or tipmember 609 having a distal end 602 a. The tip 609 may include a bodyportion configured to secure to the catheter, e.g., within the lumen 618as shown. The tip 609 may be secured, e.g., bonded, to the catheter body606 via any acceptable technique.

The closed tip 609 may form the distal end 602 a of the catheter andaxially seal the distal end of the catheter body 606 as shown in FIG.11A. One or more nonaxial, e.g., side flow, openings 616 may be formedin the closed tip 609 to permit side exiting flow of therapeutic agentfrom the catheter in a manner similar to the catheters 200, 200′, 300,400, 500, and 550 described above. In one embodiment, the tip is a madefrom tantalum and has an O.D. of about 0.041 in and an I.D. of about0.020 in, while the side flow opening(s) 416 are laser holes having adiameter of about 0.0002 in. By providing holes of this size, a 1-2 psibackpressure may be created in the catheter during CED infusion. Onceagain, this embodiment is exemplary only and catheters having componentssized and configured differently are certainly possible withoutdeparting from the scope of the invention.

The catheter 600 may further include an inflatable balloon 632 attachedat or near the distal end of the catheter body. In one embodiment, theballoon 632 may be made from a relatively flexible and resilientmaterial such as urethane. By utilizing a resilient material, theballoon may constrict and lie generally against the body 606 of thecatheter as shown in FIG. 11A when it is deflated. However, wheninflated, the balloon may expand to form a cup as shown in FIG. 11B. Theballoon 632 may be secured, e.g., thermally bonded, to the body 606 ofthe catheter as represented in the figures. In one embodiment, theballoon 632 may have a maximum outer diameter of about 0.08 in (whenused with a catheter body otherwise sized and configured as describedabove with reference to the catheter 200).

When the balloon 632 is inflated, it may form an obstructive element,e.g., undercut ledge 620. As with the ledge 520, the ledge 620 may, insome applications, assist with reduction of backflow. Moreover, like thecup 532, the cup formed by the balloon 632 may generate a compressiveseal with the immediately surrounding tissue. This seal may furtherassist in reducing catheter backflow. As with the prior embodiments, theledge 620 may be offset from the end 602 a by a predetermined distance614 (e.g., about 0.4 in).

Once implanted (e.g., via a cannula (not shown) and after the cannula iswithdrawn), the catheter 600 may be reconfigured from theballoon-deflated configuration of FIG. 11A to the balloon-inflatedconfiguration of FIG. 11B. In one embodiment, inflation is initiated bythe infusion process itself. For example, the catheter body 606 maydefine one or more openings 611 in fluid communication with the sealedcompartment formed by the balloon 632. Due to the backpressure resultingfrom the restrictive orifice 616, the balloon may inflate to itscup-shaped configuration of FIG. 11B once infusion begins. The balloon632 may, correspondingly, deflate when infusion pressure is removed. Thecatheter 600 may be removed, in one embodiment, by placing a removalcannula (not shown) over the body and the deflated balloon andwithdrawing the catheter from the proximal end. Alternatively, thecollapsed balloon may simply be withdrawn with the catheter byapplication of a traction force (e.g., without the need for a removalcannula).

FIG. 12 illustrates an enlarged view of a distal portion, e.g., a distalportion 702 of an IPA catheter 700 in accordance with still yet anotherembodiment of the invention. The catheter 700 may, except as describedbelow, be similar in many respects to the catheters already describedherein. For example, the catheter 700 may include a body 706 and aninsert, e.g., closed tip 709, similar in many respects to the body 606and tip 609 discussed above. The tip 709 may include a body portion thatbonds or is otherwise secured to a lumen 718 of the body 706. The closedtip may further include one or more nonaxial, e.g., side flow, openings716 to permit the delivery of therapeutic substance to surroundingtissue.

The catheter 700 may further include an obstructive element. In theillustrated embodiment, the obstructive element could be formed by ahydrogel coating 732 applied to a portion of the catheter body. Thehydrogel coating 732 may form an expanding gel upon contact with water,bodily fluids, etc. This gel may fill the voids between the catheterbody and the surrounding tissue and thus form an obstructive barrier tobackflow similar to the barrier provided by the ledge 620 describedabove. While illustrated without a structural ledge, the hydrogelcoating could be combined with any of the other anti-backflowembodiments described herein, e.g., the ledges 220, 320, and 420 of thecatheters 200, 300, and 400, respectively.

Although not shown herein, various techniques (e.g., use of a stylet)may be utilized with any of the embodiments described herein to assistwith stiffening of the catheter during surgical implantation.Furthermore, while specific embodiments are described and illustratedherein, various characteristics of these illustrative catheterassemblies (such as the diameter of the outer surface of theneedle/insert, the diameter of the outer surface of the body, and thepreset distance) may be varied. These parameters may be selected tominimize or reduce backflow along the catheter during therapy deliverysuch as during CED of therapeutic agent to a target tissue region of amammalian brain.

As a result, embodiments of the present invention may also be directedto methods for delivery (CED delivery) of a therapeutic substance to atarget tissue region (e.g., to a patient's brain) using a catheterassembly in accordance with embodiments of the present invention. Forexample, a catheter assembly as shown and described herein (e.g.,catheter assembly 300) may be provided. The catheter assembly may bepositioned such that a distal end of the tubular needle is implantedwithin the target tissue region. A therapeutic substance may be infusedinto the target tissue region through the lumen (e.g., 318) via CED fromthe side flow apertures (e.g., 316) of the catheter assembly at asubstantially constant flow rate and for a predetermined period of time.Where the catheter assembly, e.g., distal end of the catheter assembly,is implanted in or near a target tissue region, CED of the therapeuticagent may thus be administered using an assembly configured to assistwith the reduction of backflow of the therapeutic agent. Accordingly,the therapeutic substance may disperse into the target tissue regionprimarily in a spherical pattern emanating outwardly from or near theside flow apertures without significant backflow occurring along thecatheter track.

EXAMPLE

A baseline analysis was conducted to determine backflow characteristicsof a uniform diameter, axial flow flexible catheter. In particular, acatheter having uniform inner and outer diameters was selected forimplantation in vivo into sheep brain specimens. These catheters weremade from 80 Shore A durometer urethane and each had an inner diameterof about 0.024 in and an outer diameter of about 0.041 in. In thesetests, the catheters were implanted into the tissue of four specimens(two into the putamen and two into the white matter) andgadolinium-bound albumin contrast agent infusate was acutelyadministered via the catheter.

For the first test, the infusate was administered at 0.5microliters/minute. A second test administered the infusate at a flowrate of 2.5 microliters/minute, while a third test was run at 5microliters/minute. Each test was administered at its particularconstant flow rate for a period of seven days using a SyncroMed® IIprogrammable pump. The tissue samples were then examined under MRI. Oneof the four samples showed backflow at a flow rate of 0.5microliters/minute. All four specimens showed backflow at 2.5microliters/minute, and three showed backflow at 5 microliters/minute(no data was collected on the fourth sample at this highest flow rate).

Backflow was recognized by clearly defined flow of the contrast agentalong the catheter delivery track, indicating a potential break in thefluidic seal between the catheter and the surrounding tissue. In fact,in some instances the infusate was detected even at the catheterinsertion point into the specimen, indicating catastrophic backflow(e.g., along the entire catheter length). FIGS. 13A-13B and 13C-13D showthe two putamen and two white matter infusions, respectively, for the2.5 microliters/minute flow rate tests. The elongate white sections inthese views illustrate back flow of the contrast agent along thecatheter track.

These uniform diameter catheters were then implanted in vitro into fourcadaveric sheep brain tissue samples to a depth of about 0.59 in. Evansblue dye was infused at a flow rate of about 0.5 microliters/minute andincreased in steps every ten minutes until catastrophic backflow wasdetected (e.g., dye was observed emerging from the entry point of thecatheter into the brain tissue). The infusion device used was a modelPHD 2000 syringe pump from Harvard Apparatus of Holliston, Mass., USA.Three of the four samples indicated catastrophic backflow at the initialflow rate of 0.5 microliters/minute, while the fourth sample indicatedcatastrophic backflow at about 5 microliters/minute.

Thereafter, catheter assemblies in accordance with embodiments of thepresent invention (catheter assemblies configured generally as shown anddescribed with respect to the assembly 300 of FIGS. 4A-4D) were testedin vitro in four cadaveric sheep brain tissue samples in a mannersimilar to the in vitro uniform diameter catheter tests. In these testsusing catheter assemblies constructed in accordance with principles ofthe present invention, all four assemblies showed no catastrophicbackflow at rates up to about 30 microliters/minute.

Catheter assemblies constructed in accordance with embodiments of thepresent invention were then tested in vivo in non-human primate brains.In these tests, a catheter assembly was used that was, once again,configured generally as shown and described with respect to the assembly300 of FIGS. 4A-4D. The catheters were implanted through the cranium andtheir proximal ends anchored relative thereto with silicone elbows.These assemblies used a catheter body 306 made from 80 Shore A durometerurethane having an inner diameter of about 0.024 in and an outerdiameter of about 0.041 in. They further incorporated a guide tube 308made of PEEK with a length (including the flange 310) of about 0.4 in.The needle 312 was a 33 gage needle made from 80 Pt-20 Ir alloy with adistal tip 302 a sealed via an orbital riveting operation. It had twoside flow apertures 316 of about 0.004 in diameter and located about0.015 in from the sealed distal tip 302 a. The preset distance 314 wasabout 0.2 in. In a one-day acute infusion test, three subjects wereinfused with 1.0 microliter/minute using gadolinium (available under thetrade name Omniscan from GE Healthcare of Chalfont St. Giles, UnitedKingdom) contrast agent for a period of about six hours (for a totalinfusion of 360 microliters) using the model PHD 2000 syringe pump.Thereafter, the flow rate was increased to 30 microliters/minute for aperiod of three minutes (for a total of 90 microliters). Using magneticresonance imaging, no discernable backflow was observed at either flowrate in the test subjects. FIG. 14 illustrates an exemplary MRI scanfrom one test specimen. As shown in this view, two white circular areasare seen emanating outwardly from near the distal end of the catheterand illustrate the infusate distributions. The larger area illustratesthe infusate distribution from the six hour infusion, while the smaller,more concentrated area illustrates the infusate distribution resultingfrom the three minute infusion. As this figure illustrates, thereappears to be little or no indication of contrast agent flowing alongthe catheter track beyond the visible distribution areas, indicatingthat little if any significant backflow occurred (note: one test subjectindicated possible catheter movement during testing while anothercatheter developed a leak at its proximal end coupling).

In a chronic seven day infusion test, catheter assemblies were implantedwithin the brains of six non-human primates and gadopentetatedimeglumine contrast agent (available under the trade name Magnevistfrom Bayer HealthCare Pharmaceuticals of Wayne, N.J., USA) was infused(using a SyncroMed® II programmable pump) at various flow rates from 0.1to 1.0 microliters/minute for a period of seven days (for a total of 10milliliters infused). Once again, no significant backflow was observedat these flow rates, although one subject did show signs of cathetermovement as a result of test anchoring configurations that werepotentially ill-suited to such chronic treatment. In a correspondingtoxicity study, 26 non-human subjects were infused at 0.3microliters/minute with various concentrations of siRNA for up to 28days (for a total of 12 milliliters infused). During this test, nosignificant backflow was observed in the subjects (4 subjects did notindicate any flow at all through the catheter, indicating possibleplugging, e.g., tissue ingrowth, of the catheter prior to or duringtesting).

Catheters constructed in accordance with embodiments of the presentinvention may thus reduce catheter backflow when compared toconventional catheter constructions. Various design parameters arebelieved to contribute to this reduced backflow. For instance, it isbelieved that the relatively small diameter (e.g., 33 gage) of theneedle may be advantageous in reducing backflow when compared to largercatheters of uniform diameter. Moreover, embodiments of the presentinvention may potentially benefit from the obstruction of flow from theneedle tip as provided by obstructive elements such as those shown anddescribed herein (e.g., the step formed by the smaller diameter needlejoining to the relatively larger catheter body). Still further,catheters in accordance with embodiments of the present invention may,instead of providing axial flow, provide one or more side flowopening(s) proximate to, but offset from, the distal tip. These sideflow openings may also contribute to a reduction in backflow.

The complete disclosure of the patents, patent documents, andpublications cited in the Background, the Detailed Description ofExemplary Embodiments, elsewhere herein are incorporated by reference intheir entirety as if each were individually incorporated.

Illustrative embodiments of this invention are discussed and referencehas been made to possible variations within the scope of this invention.These and other variations, combinations, and modifications in theinvention will be apparent to those skilled in the art without departingfrom the scope of the invention, and it should be understood that thisinvention is not limited to the illustrative embodiments set forthherein. Rather, the invention is limited only by the claims providedbelow, and equivalents thereof.

What is claimed is:
 1. A catheter assembly comprising: a flexibletubular catheter body having proximal and distal ends, the bodycomprising an inner surface defining a lumen extending between theproximal and distal ends; and a rigid tubular needle partially locatedwithin the lumen of the body and extending outwardly from the distal endof the body, the needle comprising: a nonporous outer surface defined bya diameter that is less than a diameter of an outer surface of the body;a proximal end comprising a flange having a diameter larger than thediameter of the outer surface of the needle, the flange fixed relativeto the inner surface of the body; and a sealed distal tip located apreset distance beyond the distal end of the body, the needle defining aside flow aperture formed along the outer surface of the needle andproximate to, but offset from, the sealed distal tip, the side flowaperture in fluid communication with the lumen of the body; and a guidetube interposed between the proximal end of the needle and the innersurface of the body, wherein the proximal end of the needle is fixeddirectly to an inner surface of the guide tube and the guide tube isfixed to the body.
 2. The assembly of claim 1, wherein the catheter bodycomprises a shearable material.
 3. The assembly of claim 1, wherein theflange of the needle is fixed directly to the inner surface of the body.4. The assembly of claim 1, wherein the needle is fused to the guidetube.
 5. The assembly of claim 1, wherein the needle comprises aplatinum-iridium alloy.
 6. A catheter assembly comprising: a flexibletubular catheter body having proximal and distal ends, the bodycomprising an inner surface defining a lumen extending between theproximal and distal ends; a guide tube fixed to the inner surface of thebody near the distal end of the body; a tubular needle fixed to an innersurface of the guide tube and extending outwardly from a distal end ofthe guide tube, the needle comprising: an outer surface defined by adiameter that is less than a diameter of an outer surface of the body; aproximal end forming a flange; and a sealed distal tip located a presetdistance beyond the distal end of the guide tube, the needle defining aside flow aperture formed along the outer surface of the needle andproximate to, but offset from, the sealed distal tip, the side flowaperture in fluid communication with the lumen of the body; wherein theinner surface of the guide tube defines a stepped bore forming a land tocontact the flange of the needle.
 7. The assembly of claim 6, whereinthe flange of the needle is fixed directly to the inner surface of theguide tube.
 8. The assembly of claim 7, wherein the flange of the needleis fused to the inner surface of the guide tube.
 9. The assembly ofclaim 6, wherein a ratio of the diameter of the outer surface of thebody to the diameter of the outer surface of the needle is about 4:1 toabout 6:1.
 10. The assembly of claim 6, wherein the guide tube furthercomprises a sleeve portion having an outer surface, the outer surfacedefining one or more circumferential grooves into which inwardlyprotruding portions of the body extend.
 11. The assembly of claim 6,wherein the distal end of the guide tube comprises a flange configuredto abut the distal end of the catheter body.
 12. The assembly of claim6, further comprising a spacer positioned within the body such that amale portion of the spacer slides into a female portion of the guidetube to mechanically secure the needle in place relative to the catheterbody.
 13. The assembly of claim 12, further comprising a gap between adistal end of the spacer and a bottom of the female portion of the guidetube thereby permitting some slight axial movement of the needle. 14.The assembly of claim 12, wherein the spacer is positioned to press theneedle against the guide tube.